Several points within the drug approval process were seen by industry as potential market barriers to product development in this field. However, as a group, none were viewed as major barriers that could not be surmounted, especially if the market barriers cited as critical ones above were lowered or eliminated.

For two of the pharmaceutical companies interviewed, the cost of funding the necessary clinical trials for obtaining FDA approval was seen as a minor barrier to cocaine pharmacotherapy development. However, the pharmaceutical company that reported that the science base was not a barrier also reported that the regulatory aspects of development would not preclude moving ahead, so long as the science base and the financial market potential were evident. Also, one of the VC firms interviewed stated that drug regulation would not be a barrier if the market potential of the drug was very favorable.

Three of the four case study drugs were for patient populations perceived to be difficult to study for a variety of reasons (e.g., patient recruitment, compliance, and co-morbidities). For example, patient compliance has been seen as a barrier to the success of naltrexone in both the heroin addiction and alcoholism markets, because the drug is not effective unless patients take part in a treatment program with a more intensive psychosocial component than for other pharmacotherapies. Compliance is often an issue when treating patients with schizophrenia, primarily because they may not recognize their illnesses or understand the need for treatment. In addition, alcoholics and other substance abusers may also have severe co-morbidities (e.g., hepatitis or depression), which may lead to poor clinical trial outcomes or adverse events that are unrelated, but wrongly attributed, to the study medication. Finally, researchers involved in the development of LAAM and naltrexone had difficulty recruiting patients because methadone maintenance clinics were unwilling to refer patients to clinical trials for fear of lowering their patient census and associated reimbursement.

Representatives of two companies stressed that cocaine abuse and addiction drugs in the pipeline need better access to patients for conducting clinical trials. A representative of another company described how adverse effects experienced by cocaine patients with multiple co-morbidities could be improperly attributed to its investigative treatments. Although pharmaceutical company representatives viewed these patient-related difficulties as real problems, they did not regard these problems as absolute barriers that could not be overcome given other incentives for entering the market.

The uncertainty associated with designation of required clinical endpoints to be used in clinical trials of medications for cocaine addiction was cited as a market barrier, though not a major one. Two pharmaceutical company interviewees identified this ambiguity as a potential barrier, and one company representative expressed some concern that "chasing a moving target" could increase the costs of conducting clinical trials. However, the pharmaceutical company interviewees were not aware of the FDA's current efforts to update its draft guidance for trials of drugs to treat cocaine addiction.

The case study of naltrexone demonstrated the difficulty of convincing providers and patients that a reduction in use of heroin or alcohol can result in favorable health outcomes. Although naltrexone blocks the effects of both heroin and alcohol, it does not prevent patients from using these substances. Researchers noticed that because patients using naltrexone did not experience the euphoric effects of heroin or alcohol, they had less incentive to inject heroin or drink alcohol, and their volume of use was reduced. Many provider and patient support groups have expressed that total abstinence is the only acceptable cure.

DEA regulation was not generally cited by pharmaceutical company representatives as a market barrier. One interviewee mentioned the potential risk of exposing an existing successful product used for other indications to cocaine treatment. The company indicated that the increase in development costs of the drug and the potential for rescheduling of the drug could restrict the market opportunities for its original indication and market.

The case study of LAAM, which is regulated by the DEA as a Schedule II drug, demonstrates how DEA regulation can be a hurdle for drug development. This regulation places severe restrictions on distribution channels, primarily in order to prevent the drug from being diverted to the black market. DEA scheduling prevents a drug from being marketed in a state until that state has rescheduled the drug, and state rescheduling could delay product marketing by years.

It is highly unlikely that an existing product would meet the criteria for being rescheduled by the DEA. In order for a currently marketed product to be rescheduled because of its use in cocaine dependent persons, it would have to meet two criteria: 1) the drug must have abuse liability, and 2) the drug must be classified as a narcotic. While methadone and LAAM meet these criteria, naltrexone is not scheduled. In addition, products with abuse potential are scheduled at the time of their NDA approval, and if an existing product showed higher or lower than expected abuse liability after marketing, it could be rescheduled upwards or downwards, regardless of whether it ever was used in a cocaine dependent population (Cummings, 1997).

The clozapine case study demonstrates that special requirements for approved use and other atypical restrictions can pose significant market barriers. Clozapine has a potentially fatal side-effect, agranulocytosis, that warrants strict patient monitoring. This contributed to clozapine's being approved as a second- or third-line therapy, i.e., for patients who are resistant to other treatments. The strict weekly monitoring of patients on clozapine increases the cost of treatment. Sandoz originally linked sales of the drug to its Clozaril Patient Monitoring System at a cost of almost $9,000 per patient per year, severely impeding the ability and willingness of payers to purchase this treatment and dampening sales.

Two market barriers related to drug marketing were identified. As previously described, the possibility of the pharmacotherapy being distributed through publicly-funded treatment centers rather than through physician offices was a concern of the pharmaceutical companies because of the companies' limited access to patients.

Variations in federal, state and local regulations have proven to be market barriers in the case of LAAM. LAAM is the most highly regulated of the drugs (DEA Schedule 2), whereas Nicorette is the least regulated (available over-the-counter). DEA regulation of LAAM has limited market penetration by restricting delivery of LAAM to methadone maintenance clinics. In contrast, with its far less stringent regulation, Nicorette is readily available to its large target population.

Social stigma of drug abusers was cited as a market barrier by representatives of two of the pharmaceutical companies, though it is regarded as surmountable if the commercial and scientific viability of the product is favorable. The pharmaceutical companies that identified social stigma as a barrier were familiar and sympathetic to the case experience of Eli Lilly and methadone, in which the drug's original analgesia market plummeted after people associated methadone with heroin addiction treatment.

Representatives of one of the pharmaceutical companies that has a strong CNS portfolio expressed concern that the negative image of the drug abuse population would hinder the likelihood of a pharmacotherapy's financial success. Further, one company representative indicated that if a highly promising or approved drug for a non-substance abuse CNS disorder showed potential effectiveness for treating cocaine addiction, the company would be very circumspect about pursuing the cocaine indication for fear that any adverse events or stigma associated with the substance abuse indication would threaten the market for the original indication.

One pharmaceutical company interviewee suggested that social stigma can be circumvented by renaming drugs for cocaine indications. Another interviewee suggested that future progress of the science base and pharmacology may enable designating different drugs from a class of closely related yet distinct molecules, all of which would have same or similar CNS actions. Thus, one molecule could be designated as a cocaine medication while another from the same class could be designated for another CNS indication, thereby avoiding the problem of attempting to market a molecule for a cocaine indication that is effective for another CNS indication.

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